CN118401528A - GLP-1 agonist intermediate, preparation method thereof and application thereof in medicines - Google Patents

Abstract

The invention relates to a preparation method of a compound shown in a formula (I) and an intermediate thereof, which has the advantages of mild reaction conditions, simple operation, high reaction yield, high product purity and convenient post-treatment, and is suitable for industrial production.

Description

A GLP-1 agonist intermediate and its preparation method and use in medicine Technical Field

The present invention relates to a method for preparing a compound represented by formula (I) and an intermediate thereof. The method has mild reaction conditions, simple operation, high reaction yield, high product purity, convenient post-treatment, and is suitable for industrial production.

Background technique

Type 2 diabetes is a chronic metabolic disease, formerly known as non-insulin-dependent diabetes, accounting for more than 90% of diabetic patients. There are six main types of drugs for type 2 diabetes: biguanides, sulfonylureas, thiazolidinedione, DPP-4 receptor inhibitors, SGLT-2 receptor inhibitors, and GLP-1 analogs. Among them, GLP-1 is a 30-amino acid long incretin hormone secreted by L cells in the intestine. Studies have shown that GLP-1 plays an important role in regulating postprandial blood sugar. It stimulates the secretion of glucose-dependent insulin in the pancreas by stimulating the transcription of important genes for glucose-dependent insulin secretion, thereby increasing glucose absorption, inhibiting the secretion of glucagon, and reducing hepatic glucose output. In addition, GLP-1 can also promote β-cell proliferation, delay gastric emptying, slow small intestinal motility, and delay food absorption. As a result, GLP-1 has become one of the main therapeutic drugs for type 2 diabetes. However, the GLP-1 and its analogs that have been marketed are all polypeptides, and the inherent characteristics of polypeptides have brought great limitations to their application. Based on this, the development of highly bioavailable oral small molecule GLP-1 receptor agonists has become a hot topic in diabetes drug development in recent years.

WO2021249492A1, WO2021244645A1, and CN113801136A describe a class of compounds having GLP-1 activity, wherein It can be used as a key intermediate for the synthesis of this type of product.

WO2021249492A1 (publication date: 2021.12.16) discloses another intermediate B-5, which is prepared by route 1 using B-5-1 as the starting material. This preparation method has the problems of expensive starting materials, low reaction conversion efficiency, difficult separation and purification, inability to avoid column chromatography, and difficulty in achieving industrial scale-up production.

Route 1:

CN113801136A (publication date: 2021.12.17) discloses another intermediate 1e, which is prepared by the following 1a (as the starting material through the reaction of route 2. This route has the problems of expensive starting materials, long chiral fragment synthesis route, poor stability of intermediates, difficulty in scale-up production, and safety hazards (palladium carbon/hydrogen reduction in the second step).

Route 2:

Therefore, it is necessary to develop a route for preparing compound (I) with mild reaction conditions, simple operation, high reaction yield, high product purity, convenient post-treatment, and suitable for industrial production.

Summary of the invention

The object of the present invention is to provide a method for preparing a compound represented by formula (I) and an intermediate thereof, wherein the method has low-cost starting materials, mild reaction conditions, simple operation, high yield, high product purity, convenient post-treatment, and is suitable for industrial production.

The present invention provides a method for preparing a compound of formula (I), wherein the compound of formula (I) is prepared from the compound of formula (II) by step (a).

wherein R is selected from H, C _1-4 alkyl or C _6-10 carbocycle, wherein the alkyl or C _6-10 carbocycle is optionally further substituted by 0 to 4 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or C _6-10 carbocycle; preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, hexyl, phenyl or -CH ₂ -phenyl; more preferably, R is selected from propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, hexyl, phenyl or -CH ₂ -phenyl.

Y is selected from halogen, and when Y is selected from Br, R is not methyl; preferably, Y is selected from Cl.

In some embodiments of the method for preparing the compound shown in (I), the step (a) includes the use of a halogenating agent and an initiator, and the halogenating agent is selected from N-haloamide; preferably, the halogenating agent is selected from N-chloroacetamide, dibromohydantoin, dichlorohydantoin, N-bromoacetamide, N-bromosuccinimide, N-chlorosuccinimide or N-iodosuccinimide; more preferably, the halogenating agent is selected from N-bromosuccinimide, N-chlorosuccinimide or N-iodosuccinimide; more preferably, the halogenating agent is selected from N-chlorosuccinimide; the initiator is selected from peroxides or symmetrical azo compounds; preferably, the initiator is selected from di-tert-butyl peroxide, dibenzoyl peroxide, azobisisobutyronitrile; more preferably, the initiator is selected from azobisisobutyronitrile.

The present invention provides a method for preparing a compound represented by formula (II), wherein the compound represented by formula (III-1) and the compound represented by formula (III-2) are reacted by step (b) to obtain the compound represented by formula (II).

wherein R is selected from H, C _1-4 alkyl or C _6-10 carbocycle, wherein the alkyl or C _6-10 carbocycle is optionally further substituted by 0 to 4 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or C _6-10 carbocycle; preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, hexyl, phenyl or -CH ₂ -phenyl; more preferably, R is selected from propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, hexyl, phenyl or -CH ₂ -phenyl.

In some embodiments of the method for preparing the compound shown in (II), the step (b) includes the use of an alkaline reagent, and the alkaline reagent is selected from one or more of 1,8-diazabicycloundec-7-ene, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, sodium hydride, sodium hydroxide and potassium hydroxide.

In some embodiments of the method for preparing the compound shown in (I) or (II) of the present invention, the step (a) or step (b) also includes the use of a solvent, and the solvent is selected from one or more of alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents, sulfone solvents and water.

In some embodiments of the method for preparing the compound shown in (I) or (II), the solvent in step (a) or step (b) is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, n-butanone, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, ethyl ether, tetrahydrofuran and water.

In some embodiments of the method for preparing the compound shown in (I) of the present invention, the solvent in step (a) is selected from 1,2-dichloroethane or acetonitrile.

In some embodiments of the method for preparing the compound shown in (II) of the present invention, the solvent in the step (b) is selected from methanol.

The present invention provides a method for preparing a compound of formula (III), comprising the following steps: 1) preparing a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2) through step (d); 2) preparing a compound of formula (III) from the compound of formula (IV) through step (c),

X is selected from F, Cl, Br, I, p-toluenesulfonyloxy, methanesulfonyloxy, p-nitrobenzenesulfonyloxy, o-nitrobenzenesulfonyloxy or trifluoromethanesulfonyloxy.

The invention relates to a method for preparing a compound of formula (III). Step (d) comprises the use of a catalytic agent, wherein the catalytic agent is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, 1,8-diazabicycloundec-7-ene, diisopropylethylamine, triethylamine, potassium carbonate, potassium phosphate, cesium carbonate, sodium carbonate, sodium phosphate and sodium hydride; and step (c) comprises the use of a metallizing agent and N,N-dimethylformamide, wherein the metallizing agent is selected from _R1Li , _R1MgX1 or magnesium, wherein _X1 is selected from F _, Cl, Br and I, and _R1 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl and phenyl.

The present invention relates to a method for preparing a compound of formula (III), wherein the step (d) or (c) further comprises the use of a solvent, wherein the solvent is selected from one or more of amide solvents, alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents, sulfone solvents and water.

The present invention relates to a method for preparing a compound of formula (III), wherein the solvent in step (d) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, ethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, methanol, ethanol, isopropanol, sec-butanol, n-butanol, tert-butanol, n-propanol , trifluoroethanol, hexafluoroisopropanol, acetone, butanone, ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, dimethyl sulfoxide, acetonitrile, propionitrile; in step (c), the solvent is selected from tetrahydrofuran, 1,4-dioxane, ether, isopropyl ether, methyl butyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, benzene, toluene, xylene, chlorobenzene, dichlorobenzene.

The present invention relates to a method for preparing a compound of formula (III), wherein the solvent in the step (d) is selected from N,N-dimethylformamide; and the solvent in the step (c) is selected from tetrahydrofuran.

The present invention provides a method for preparing a compound of formula (III), comprising the step of preparing a compound of formula (III) from a compound of formula (IV) through step (c), wherein the solvent and reagent included in step (c) are the same as the solvent and reagent in the aforementioned step (c).

The present invention provides a method for preparing a compound of formula (IV), comprising the step of preparing the compound of formula (IV) from the compound of formula (V-1) and the compound of formula (V-2) through step (d), wherein the solvent and reagent in step (d) are the same as the solvent and reagent in the aforementioned step (d).

The present invention also provides a compound represented by formula (I) and a salt thereof,

wherein Y is selected from Cl;

R is selected from propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, hexyl, phenyl or _-CH2 -phenyl.

The present invention also provides a compound represented by formula (III-1) and a salt thereof,

The present invention also provides a compound represented by formula (IV) and a salt thereof,

The method for preparing the compound represented by formula (I) provided by the present invention has the advantages of cheap and readily available starting materials, easy to achieve reaction conditions, simple operation, reasonable cost distribution, convenient post-treatment, and suitability for industrial production.

Unless stated otherwise, the terms used in this specification and claims have the following meanings.

The method of using extraction in the post-treatment of the reaction in the present invention is a conventional method in the art. The solvent for extraction can be selected according to the solubility of the product and the solubility of the organic solvent in water. Common extraction solvents include but are not limited to one or more mixed solvents of dichloromethane, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, ether, isopropyl ether, methyl tert-butyl ether, methanol and ethanol. The number of extractions can be appropriately increased or decreased according to the amount of product remaining in the aqueous phase. The organic phase after extraction is optionally further treated with conventional washing or/and drying in the art.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Halogen" refers to F, Cl, Br or I.

"Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups appearing herein are defined in accordance with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.

"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be a monocyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

The salt of a compound refers to a salt obtained by reacting a free acid with an inorganic base or an organic base, or a salt obtained by reacting a free base with an inorganic acid or an organic acid.

"Alcohol solvent" refers to a solvent containing hydroxyl groups in its molecular structure. Non-limiting examples include ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, sec-pentanol, 3-pentanol, isopentanol, tert-pentanol, n-hexanol and cyclohexanol.

“Ether solvents” refer to solvents with ether bonds in their molecular structure. Non-limiting examples include tetrahydrofuran, 2-methyltetrahydrofuran, ethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, diisopropyl ether, ethyl butyl ether, dibutyl ether, diamyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and anisole, etc.

"Aromatic hydrocarbon solvents" refer to solvents containing 0-3 heteroatoms (heteroatoms selected from O, S or N) and aromatic rings in their molecular structures. Non-limiting examples include benzene, pyridine, toluene, ethylbenzene, xylene, chlorobenzene and o-dichlorobenzene.

“Halogenated alkane solvents” refer to alkane solvents containing halogens (fluorine, chlorine, bromine, iodine) in their molecular structures. Non-limiting examples include dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, carbon tetrachloride, pentachlorohexane, 1-chlorobutane and bromoform.

"Alkane solvent" refers to a solvent containing only alkanes in its molecular structure, and non-limiting examples include n-hexane, n-heptane, n-octane, n-pentane, cyclohexane and cycloheptane.

"Ester solvents" refer to solvents containing carboxylic acid esters in their molecular structure. Non-limiting examples include ethyl acetate, isopropyl acetate, triacetin, ethyl acetoacetate, isoamyl acetate, isopropyl acetate, n-butyl acetate, n-propyl acetate, n-amyl acetate, methyl acetate, sec-butyl acetate, butyl formate, propyl formate, n-amyl formate and diethyl carbonate, etc.

"Ketone solvent" refers to a solvent containing a ketone carbonyl group in its molecular structure. Non-limiting examples include acetone, butanone, acetophenone, methyl isobutyl ketone, 2,6-dimethyl-2,5-heptadien-4-one, 3,5,5-trimethyl-2-cyclohexenone and mesityl oxide, etc.

"Nitrile solvent" refers to a solvent containing a cyano group in its molecular structure, and non-limiting examples include acetonitrile, propionitrile, butyronitrile and benzyl cyanide.

"Amide solvents" refer to solvents containing amides in their molecular structure. Non-limiting examples include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, hexamethylphosphoramide, and N-methylpyrrolidone.

"Polar aprotic solvent" refers to a solvent that does not contain hydrogen atoms directly connected to electronegative atoms and does not have hydrogen bonding ability. Non-limiting examples include acetone, dimethyl sulfoxide, HMF (hydroxymethyl furfural), crown ethers, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone, etc.

"Polar protic solvents" refer to solvents capable of hydrogen bonding (because they contain at least one hydrogen atom directly attached to an electronegative atom (e.g., an O-H or N-H bond)), non-limiting examples of which include methanol, water, ethanol, ammonia, acetic acid, and the like.

"Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, including instances where the event or circumstance occurs or does not occur.

The reaction process of the present invention is tracked by HPLC, HNMR or thin layer chromatography to determine whether the reaction is completed.

In the present invention, the internal temperature refers to the temperature of the reaction system.

Detailed ways

The technical solution of the present invention is described in detail below in conjunction with embodiments, but the protection scope of the present invention includes but is not limited to them.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm) was used for HPLC analysis.

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF ₂₅₄ or Qingdao GF ₂₅₄ silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

The ratio shown in the silica gel column chromatography of the present invention is a volume ratio.

The room temperature is 20℃～30℃.

Boc: tert-butoxycarbonyl;

Ts: p-toluenesulfonyl;

Cbz: benzyloxycarbonyl;

TMS: trimethylsilyl.

OMs: methanesulfonyloxy;

OTs: p-toluenesulfonyloxy;

ONs: p-nitrobenzenesulfonyloxy or o-nitrobenzenesulfonyloxy;

OTf: trifluoromethanesulfonyloxy;

i-Pr: isopropyl;

Pr: n-propyl;

i-Bu: isobutyl;

t-Bu: tert-butyl;

n-Amyl: n-pentyl;

t-Amyl: tert-amyl;

n-Hex: n-hexyl;

NCS: N-chlorosuccinimide;

AIBN: azobisisobutyronitrile;

DBU: 1,8-diazabicycloundec-7-ene;

HOBt: 1-hydroxybenzotriazole;

DMF: N,N-dimethylformamide;

THF: tetrahydrofuran;

DCM: dichloromethane.

Example 1

(S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (A1)

methyl(S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate(A1)

Step 1: 4,5-Dibromo-2-methyl-1H-imidazole (A1b)

4,5-dibromo-2-methyl-1H-imidazole(A1b)

Add A1a (100 g, 1.22 mol) to DMF (1.5 L), then add potassium bicarbonate (366 g, 3.3 mol). Cool to an internal temperature of -15 °C, slowly add liquid bromine (584 g, 3.3 mol), and control the internal temperature below -5 °C. The addition is completed in about 2.5 hours, and the temperature is restored to room temperature, then heated to 100 °C and reacted for 6 hours. The reaction solution is cooled to room temperature and slowly poured into stirred ice water (6.9 L). A large amount of white solid precipitates. Filter, wash the filter cake with water, and dry to obtain a white to light pink solid product A1b (194 g, purity: 92.0%, converted yield 61%), which can be slurried for purification or directly used in the next step.

LCMS: m/z = 240.9 [M+H] ⁺ .

Step 2: (S)-4,5-dibromo-2-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (A1c)

(S)-4,5-dibromo-2-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole(A1c)

B1 (50 g, 189 mmol) was dissolved in DMF (250 mL). A1b (46.7 g, 194.5 mmol) and DBU (57 mL, 378 mmol) were then added, and the temperature was raised to 80°C for 2 h. The reaction solution was cooled to room temperature, and 10% saline (500 mL) was added dropwise to the reaction solution. A large amount of off-white solid precipitated, which was filtered and the filter cake was washed with a small amount of water to obtain an off-white solid product A1c (45.1 g, purity: 97.4%, converted yield 75%).

LCMS: m/z = 310.9 [M+H] ⁺ .

Step 3: (S)-4-Bromo-2-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (A1d)

(S)-4-bromo-2-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde(A1d)

A1d (43.2 g, 136.5 mmol) was added to THF (250 mL), and then the temperature was lowered to -75 ° C. n-butyl lithium (94 mL, 150 mmol) was added dropwise, and the internal temperature was controlled to be lower than -65 ° C. After the n-butyl lithium was added dropwise, the reaction was kept warm for 1 hour. Then DMF (32 mL, 410 mmol) was added dropwise (the internal temperature was controlled to be lower than -65 ° C). After the addition was completed, the reaction was kept warm for 4 hours. After the reaction was completed, ammonium chloride solution was added to quench, isopropyl acetate was extracted (400 mL X 3), washed with water (400 mL X 2), and then washed with 5% NaCl solution (400 mL X 1), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain 52 g of crude product. The crude product was purified by silica gel column (Heptane:EA=4:1) to obtain product A1d (28 g, purity: 92.1%, conversion yield 73%).

¹ H NMR (400MHz, CDCl ₃ ) δ = 2.31-2.46 (m, 1H), 2.54 (s, 3H), 2.69-2.82 (m, 1H), 4.31-4.71 (m, 4H), 5.0-5.11 (m ,1H),9.66(m,1H)ppm.

LCMS: m/z = 259.1 [M+H] ⁺ .

Step 4: (S)-2-methyl-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (A1e)

methyl(S)-2-methyl-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate(A1e)

A1d (20 g, 77.2 mmol) was dissolved in dry DMF (200 mL), and silica gel (20 g, 200-300 mesh), methyl thioglycolate (24.6 g, 232 mmol) and sodium methoxide-methanol solution (72 mL, 386 mmol, 5.4 M in MeOH) were added in sequence. The mixture was heated to 75°C and kept for 1 h. After the reaction was complete, the mixture was cooled to 0°C, acetic acid was added to adjust the pH to 4, IPAc (0.5 L) was added, and the pH was adjusted to 8 with a saturated NaHCO ₃ solution. The mixture was extracted with isopropyl acetate (200 mL x 3), washed with water (200 mL x 2), and then washed with a 5% NaCl solution (200 mL x 1). The mixture was dried over anhydrous Na ₂ SO ₄ and concentrated to obtain 17 g of a crude product. The product was purified by pulping (Heptane:EA=4:1) to obtain the product A1e (12.1 g, purity: 95.7%, converted yield 56%).

¹ H NMR (400MHz, CDCl ₃ ) δ = 2.31-2.46 (m, 1H), 2.63 (s, 3H), 2.66-2.81 (m, 1H), 3.88 (s, 3H), 4.22-4.37 (m, 3H) ), 4.62 (dd, J = 14.1, 7.6 Hz, 1H), 5.09-5.21 (m, 1H), 7.67 (s, 1H) ppm.

LCMS: m/z = 267.1 [M+H] ⁺ .

Step 5: (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (A1)

methyl(S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate(A1)

At room temperature, A1e (10.0 g, 37.5 mmol) was dissolved in ACN (150 mL) solution, and then AIBN (1.2 g, 7.5 mmol) was added. The temperature was raised to 60°C, and NCS (6.5 g, 48.8 mmol) was added in batches. The addition was completed in three batches within 1 h. After the addition was completed, the reaction was continued at 60°C for 2 h. After the reaction was completed, it was cooled to room temperature, isopropyl acetate (200 mL) was added, and the mixture was washed with water (100 mL x 2), and then washed with 5% NaCl solution (100 mL x 1), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain 13.0 g of a brown-red liquid crude product (A1). The crude product and 2.5 g of activated carbon were dissolved in 25 mL of methanol, heated to 60°C, maintained for 0.5 h, and filtered while hot. The filtrate was collected and the solvent was removed under reduced pressure. 15 mL of methanol was added and heated to dissolve, 8 mL of water was added, and then the temperature was lowered to 0-10° C. for crystallization, filtered, and dried to obtain a yellow solid A1 (5.4 g, purity 94%, converted yield 45%).

¹ H NMR (CDCl ₃ , 400MHz) δ = 2.36-2.47 (m, 1H), 2.70-2.81 (m, 1H), 3.90 (s, 3H), 4.34 (dt, J = 9.2, 6.0Hz, 1H), 4.39-4.50(m,2H),4.64(td,J=7.9,6.1Hz,1H),4.87-4.98(m,2H),5.15-5.23(m,1H),7.72(s,1H).

LCMS: m/z = 301.1 [M+H] ⁺ .

Example 2

(S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (A1)

methyl(S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate(A1)

At room temperature, 2a (140 g, 0.53 mol) was dissolved in 1,2-dichloroethane (1.7 L), and then AIBN (17.50 g, 0.11 mol) was added. After the addition was completed, the temperature was raised to 60°C, and NCS (84.20 g, 0.63 mol) was added three times. After the addition was completed, the reaction was continued at 60°C for 2 h. The reaction solution was cooled to room temperature, 1 L of water was added, and the liquid was separated. The aqueous phase was extracted with 1 L of DCM, and the organic phases were combined, washed once with 1 L of water, washed once with saturated sodium chloride, and dried over anhydrous sodium sulfate to obtain 178.40 g of crude product. The crude product was dissolved in 350 ml of methanol at 60°C, and 20 g of activated carbon was added for decolorization for 0.5 h. The filtrate was filtered while hot, and the filtrate was concentrated to dryness. 200 ml of methanol was added and heated to dissolve, 70 ml of water was added, and then the temperature was lowered to 0-10°C for crystallization. The product was filtered and dried to obtain a yellow solid 2b (76.6 g, purity 96%, equivalent yield 46%).

LCMS: m/z = 301.1 [M+H] ⁺ .

In summary, the method for preparing the compound represented by formula (I) provided by the present invention has low-cost starting materials, mild reaction conditions, simple operation, high yield, high product purity, convenient post-treatment, and is suitable for industrial production.

Claims (14)

1. A method for producing a compound represented by the formula (I), wherein the compound represented by the formula (I) is produced from the compound represented by the formula (II) by the step (a);

   Wherein R is selected from H, C _1-4 alkyl or a C _6-10 carbocycle, said alkyl and C _6-10 carbocycle optionally being further substituted with 0 to 4 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or C _6-10 carbocycle;

   Y is selected from F, cl, br or I, and when Y is selected from bromine, R is not methyl.
2. A process for producing a compound of formula (II) wherein the compound of formula (II) is produced from a compound of formula (III-1) and a compound of formula (III-2) by the step (b),

   Wherein R is selected from H, C _1-4 alkyl or a C _6-10 carbocycle, said alkyl and C _6-10 carbocycle optionally being further substituted with 0 to 4 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or C _6-10 carbocycle.
3. The preparation method according to claim 1 or2, wherein,

   R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, hexyl, phenyl or-CH ₂ -phenyl.
4. The process according to claim 1, wherein step (a) comprises the use of a halogenating agent selected from the group consisting of N-haloamides (preferably N-chloroacetamide, dibromohydantoin, dichlorohydantoin, N-bromoacetamide, N-bromosuccinimide, N-chlorosuccinimide or N-iodosuccinimide) and an initiator selected from the group consisting of peroxides or symmetrical azo compounds (preferably di-t-butyl peroxide, dibenzoyl peroxide, azobisisobutyronitrile).
5. The method of claim 2, wherein step (b) comprises the use of an alkaline reagent selected from one or more of 1, 8-diazabicycloundec-7-ene, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium phosphate, cesium carbonate, sodium hydride, sodium hydroxide and potassium hydroxide.
6. The production method according to claim 1 or 2, wherein the step (a) or (b) further comprises the use of a solvent selected from one or more of an alkane solvent, an haloalkane solvent, an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, a nitrile solvent, a sulfone solvent and water.
7. The process according to claim 6, wherein the solvent in the step (a) or (b) is one or more selected from the group consisting of methylene chloride, 1, 2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, n-butanone, methyl t-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran and water.
8. A process for the preparation of a compound of formula (III), comprising the steps of: 1) Preparing a compound of formula (IV) from a compound of formula (V-1) and a compound of formula (V-2) by the step (d); 2) The compound shown in the formula (IV) is prepared into a compound shown in the formula (III) through the step (c),

   X is selected from F, cl, br, I, p-toluenesulfonyloxy, methanesulfonyloxy, p-nitrobenzenesulfonyloxy, o-nitrobenzenesulfonyloxy or trifluoromethanesulfonyloxy.
9. The process of claim 8, wherein step (d) comprises the use of a catalytic agent selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, 1, 8-diazabicycloundec-7-ene, diisopropylethylamine, triethylamine, potassium carbonate, potassium phosphate, cesium carbonate, sodium phosphate, and sodium hydride; the step (c) comprises the use of a metallizing agent and N, N-dimethylformamide, wherein the metallizing agent is selected from R ₁Li、R ₁MgX ₁ or magnesium, the X ₁ is selected from F, cl, br or I, and the R ₁ is selected from methyl, ethyl, propyl, isopropyl, N-butyl, sec-butyl, tert-butyl, N-pentyl, isopentyl, tert-pentyl, N-hexyl or phenyl.
10. The process according to claim 9, wherein the step (d) or (c) further comprises the use of a solvent selected from one or more of amide-based solvents, alkane-based solvents, haloalkane-based solvents, alcohol-based solvents, ketone-based solvents, ester-based solvents, ether-based solvents, nitrile-based solvents and sulfone-based solvents; (c) The step further comprises the use of a solvent selected from one or more of an alkane solvent, an haloalkane solvent, an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, a nitrile solvent, and a sulfone solvent.
11. The production process according to claim 10, wherein the solvent in the step (d) is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1, 4-dioxane, diethyl ether, isopropyl ether, methyl t-butyl ether, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, methanol, ethanol, isopropanol, sec-butanol, N-butanol, t-butanol, N-propanol, trifluoroethanol, hexafluoroisopropanol, acetone, butanone, ethyl acetate, isopropyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, dimethyl sulfoxide, acetonitrile and propionitrile; (c) The solvent in the step is selected from tetrahydrofuran, 1, 4-dioxane, diethyl ether, isopropyl ether, methyl butyl ether, 2-methyl tetrahydrofuran, methyl tertiary butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, benzene, toluene, xylene, chlorobenzene or dichlorobenzene.
12. A compound represented by the formula (I) and salts thereof,

    Wherein Y is selected from Cl;

    R is selected from propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, hexyl, phenyl or-CH ₂ -phenyl.
13. A compound represented by the formula (III-1) and a salt thereof,
14. A compound represented by the formula (IV) and a salt thereof,